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Background <p>Approximately 3000 adult patients are diagnosed with AML in the UK each year. Current intensive treatments are not well-tolerated by elderly patients, and the 5-year survival rate is only 5–15%, highlighting the need for novel and effective therapies. Oncolytic viruses (OVs) preferentially replicate in cancer cells, resulting in direct oncolysis and induction of innate and adaptive anti-tumour immunity. Unfortunately, the efficacy of OVs remains relatively unexplored in AML.</p> Methods <p>Using human AML cell lines, healthy-donor peripheral blood mononuclear cells (PBMC) and AML patient samples, we investigated whether combination with clinically applicable apoptotic modulators (SMAC/BH3 mimetics) can potentiate OV-induced cytokine-mediated killing.</p> Results <p>We confirmed that OVs stimulate PBMCs to produce inflammatory cytokines, which can induce AML cell death. Bystander cytokine-mediated killing was also significantly enhanced in combination with SMAC/BH3 mimetics, with the optimal combination partner varying with AML subtype. We identified interferon (IFN)-α and tumour necrosis factor (TNF)-α as potential mediators of AML cytotoxicity, and SMAC/BH3 mimetics enhanced AML cell death following direct OV infection, indicating autocrine-paracrine signalling events. Pivotally, we confirmed that apoptotic modulators were effective in combination with both Live- and UV-inactivated virus.</p> Conclusion <p>This work has identified a novel reovirus-based combination-immunotherapy for the treatment of AML.</p> <p></p>

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Apoptotic modulators enhance oncolytic virus-induced cytokine killing in acute myeloid leukaemia (AML)

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月10日

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  • Basem Askar,
  • Samuel Heaton,
  • Tyler Barr,
  • Richard Baugh,
  • Noura Alzamel,
  • Stewart McConnell,
  • Victoria A. Jennings,
  • Milene Volpato,
  • Christy Ralph,
  • Manish Jain,
  • Richard J. Kelly,
  • Christopher Parrish,
  • Fiona Errington-Mais

摘要

Background

Approximately 3000 adult patients are diagnosed with AML in the UK each year. Current intensive treatments are not well-tolerated by elderly patients, and the 5-year survival rate is only 5–15%, highlighting the need for novel and effective therapies. Oncolytic viruses (OVs) preferentially replicate in cancer cells, resulting in direct oncolysis and induction of innate and adaptive anti-tumour immunity. Unfortunately, the efficacy of OVs remains relatively unexplored in AML.

Methods

Using human AML cell lines, healthy-donor peripheral blood mononuclear cells (PBMC) and AML patient samples, we investigated whether combination with clinically applicable apoptotic modulators (SMAC/BH3 mimetics) can potentiate OV-induced cytokine-mediated killing.

Results

We confirmed that OVs stimulate PBMCs to produce inflammatory cytokines, which can induce AML cell death. Bystander cytokine-mediated killing was also significantly enhanced in combination with SMAC/BH3 mimetics, with the optimal combination partner varying with AML subtype. We identified interferon (IFN)-α and tumour necrosis factor (TNF)-α as potential mediators of AML cytotoxicity, and SMAC/BH3 mimetics enhanced AML cell death following direct OV infection, indicating autocrine-paracrine signalling events. Pivotally, we confirmed that apoptotic modulators were effective in combination with both Live- and UV-inactivated virus.

Conclusion

This work has identified a novel reovirus-based combination-immunotherapy for the treatment of AML.